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Identification of mechanisms involved in coordinated group migration

Damien Garbett

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National Institutes of Health (NIH)
Collective cell migration is a hallmark of embryogenesis, tissue development, injury response, and cancer invasion. These examples share common mechanisms which require directional responses to extracellular stimuli, cellular polarization, cytoskeletal remodeling, cell-cell adhesion, and coordination between individual cells within a group termed leaders and followers. Previous studies suggest RhoGTPases and other core polarity regulators have different roles between leaders and followers. Our preliminary work also indicates that the formation of asymmetrical cell-cell junctions is essentialfor coordination between leaders and followers during collective migration. Here, I propose to determine how RhoGTPase activity is coordinated between leaders and followers and how this results in collective migration. Specifically, I propose the following three aims: 1. Map the spatiotemporal distribution of RhoGTPase activity (RhoA, Rac1, and Cdc42) and tension forces in leader and follower cells. 2. Identify how RhoGTPase activity and polarity information is communicated between leaders and followers. 3. Examine the physiological roles of RhoGTPase regulation and coordination in three dimensional collective cell migration. This proposal seeks to identify the molecular basis of how cells are able to coordinate their polarity machinery to migrate as one cohesive group. A quantitative and systems level understanding of how cells achieve this remarkable level of coordination will reveal how complex signaling networks are regulated between neighboring cells that can be utilized to generate new therapeutic targets for vascular injury and cancer metastasis.

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